4. Medicinal plants as antibacterial agents

Numerous researchers studied the healing effects of plants and their extracts along with their beneficial effects in healthy organisms. Nowadays, plant-based therapy benefits of solid scientific support the individual chemical components or their combinations showing antimicrobial and anti-inflammatory activity, immune-stimulating potential, or anticancer effects. Since prevention is the key to good health, the researchers investigated the possibilities of using vegetal preparations to preserve health: (a) indirectly, by stimulating both innate and the adaptive immune response to antigens of various kinds and also (b) directly, by exerting either a bacteriostatic or preferably a bactericidal effect [70].

Apparently simple, the selection of plants or their extracts to be used for specific therapeutic purposes embodies the involvement of numerous factors, from health to economic impacts (Figure 2).

Figure 2. Different steps of the decision-making process in plant extract use for therapy.

#### 4.1. Plant extracts acting against bacteria indirectly: immunological uses

Due to the high diversity of MDR bacteria isolated from numerous animal sources and food of animal origin, an integrated meta-analysis of data could support the upgraded short-, medium-, and long-term strategies to control antimicrobial resistance and its further development, which in their turn are important for preventing the emergence and cross-country/

Numerous researchers studied the healing effects of plants and their extracts along with their beneficial effects in healthy organisms. Nowadays, plant-based therapy benefits of solid scientific support the individual chemical components or their combinations showing antimicrobial and anti-inflammatory activity, immune-stimulating potential, or anticancer effects. Since prevention is the key to good health, the researchers investigated the possibilities of using vegetal preparations to preserve health: (a) indirectly, by stimulating both innate and the adaptive immune response to antigens of various kinds and also (b) directly, by exerting either a

Apparently simple, the selection of plants or their extracts to be used for specific therapeutic purposes embodies the involvement of numerous factors, from health to economic impacts

continent spreading of resistant strains [69].

100 Antimicrobial Resistance - A Global Threat

4. Medicinal plants as antibacterial agents

bacteriostatic or preferably a bactericidal effect [70].

Figure 2. Different steps of the decision-making process in plant extract use for therapy.

(Figure 2).

Current trends in medicine tend to include natural products in therapy, without mixing allopathic and homeopathic treatments, the latest gaining more and more in comparison with chemically obtained compounds. The WHO list of 252 basic and essential drugs includes 11% of medications exclusively of flowering plant origin [71].

Vegetal extracts from various plant origins are used more and more, with a favorable activity in diminishing the negative impact of numerous microbial agents or in improving the innate or acquired resistance of the body to infections [17, 18, 72].

Classical therapeutic protocols supplemented with vegetal extracts could increase the protective capacity of the individuals, by their complex action mechanisms, which stimulate immunity. This pattern is actually applied in veterinary medicine, where certain stress-induced changes, caused by intensive raising/farming of food species, could be corrected in this manner [73–76]. Moreover, active principles proved to be potent in restoring the immune reactivity in individuals with induced or innate immunosuppression [77–82].

Vaccines against bacterial diseases represent one of the most powerful tools for prevention and control. Within this framework, researches on the immune stimulating activities of vegetal extractions were successful, with obvious immune modulating effects. Due to improved bioavailability as compared to conventional drugs, combined with immune modulating potential, the question on plant extracts as potential adjuvants emerged for vaccines broadly used to prevent infectious diseases, in both humans and animals. An appropriate understanding of adjuvant potential of vegetal extracts and experimental design to investigate these possibilities would lean on a good knowledge of general action mechanisms of vaccine adjuvants.

#### 4.2. Direct antibacterial activity of plant extracts

Antimicrobial effects of plant extracts on clinical isolates from farmed and pet animals and their potential use to improve health and lower the risk for humans were illustrated by experiments aiming to investigate the influence of the plant taxonomy/chemical composition on the in vitro bacteriostatic/bactericidal effects.

Plant extracts were initially proposed as supplementary means in combined antibiotic and natural therapies; therefore, the synergism between plant extracts and antibiotics was also observed in experimental studies. In a complex research carried out to establish the antimicrobial effect of certain plants: Achillea millefolium (yarrow), Caryophyllus aromaticus (clove), Melissa officinalis (lemon-balm), Ocimum basilicum (basil), Psidium guajava (guava), Punica granatum (pomegranate), Rosmarinus officinalis (rosemary), Salvia officinalis (sage), Syzygium jambolanum (jambolan), and Thymus vulgaris (thyme) on bacteria resistant from 1 to 18 antibiotics: amikacin, ampicillin, cephalothin, cefpirome, carbenicillin, cefoxitin, chloramphenicol, ceftriaxone, cefotaxime, erythromycin, gentamicin, kanamycin, lincomycin, methicillin, nalidixic acid, netilmicin, norfloxacin, nitrofurantoin, penicillin, piperacillin, rifampicin, sulfonamide, sulfamethoxazole, tobramycin, tetracycline, vancomycin (Proteus spp., Klebsiella pneumoniae, Shigella spp., Pseudomonas aeruginosa, Enterobacter aerogenes, Escherichia coli, Staphylococcus aureus) and susceptible collection strains (Staphylococcus aureus ATCC 6538, Salmonella choleraesuis ATCC 10708; Pseudomonas aeruginosa ATCC 15442), the authors indicated that clove (Caryophyllus aromaticus) and jambolan (Syzygium jambolanum) were the strongest inhibitors (64.2 and 57.1%) of the used bacterial strains. Furthermore, their activity was the most remarkable (83.3%) against the germs resistant to antibiotics, where their synergistic activity with the antibiotics was also observed. Interestingly, plants such as sage and yarrow, well known for their antiseptic properties, showed no effect on the tested MDR bacteria. Some of the plants showed in specific cases a homeopathic-like effect, i.e., clove, jambolan, pomegranate, and thyme extracts, when used in lower concentrations but combined with ineffective antibiotics against Pseudomonas aeruginosa [26, 27, 29, 83, 84].

Other well-known plants, which share immunological activity, from Compositae family, were further investigated for their antibacterial effects, following the principle of "the more the merrier." Echinacea, a popular plant in human medicine for its immune-stimulating and antiviral effects, also acts as an inhibitor for both tissue and bacterial hyaluronidase. This activity was considered to hinder the development and spreading of infection from localized

Multidrug Resistance in Zoonotic Pathogens: Are Medicinal Plants a Therapeuthic Alternative?

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Another plant family, the Lamiaceae, has numerous examples of species with antibacterial activity. The investigation of their antibacterial activity against MDR, extended spectrum beta-lactamase-positive (ESBL), Gram-negative clinical isolates (A. baumannii, K. pneumoniae, E. coli, P. aeruginosa) of ethanolic extracts of Mentha sp., Ocimum basilicum, Plectranthus barbatus, and Rosmarinus officinalis, indicated that the minimal inhibiting concentration ranged from 0.5 to 2 mg/mL, while all extracts were effective against at least two of the tested bacteria [85].

Another plant from Lamiaceae with a less investigated antibacterial influence was considered as a potential therapeutic resource in bovine mastitis. Mastitis, one of the most economically impacting diseases of dairy cows due to subclinical status and difficult diagnosis, is heavily treated with antibiotics, leading to MDR in the involved bacterial strains. The lesser antibiotic efficacy, therefore, demands for therapeutic alternatives. In a study on the antimicrobial effectiveness of Melissa officinalis on the subclinical mastitis, microbiome carried out on several Romanian dairy farms ([93]), a variety of bacteria (S. sciuri, Shigella spp. S. lentus, Acinetobacter baumannii, Chryseomonas luteola, Enterobacter cloacae, Escherichia vulneris, etc.) were isolated with an MAR index up to 0.8 against amoxicillin+clavulanate, amoxicillin, chloramphenicol, cefoperazone, ciprofloxacin, and oxytetracycline. The Melissa tincture was less effective than the same plant essential oil (11.3 3.6 versus 12.3 4.3 mm), but comparable to amoxicillin, amoxicillin/clavulanic acid, and was higher than cefoperazone (total resistance). The efficacy depended more on the strain than on the solvent type also suggesting a therapeutic alternative

Most of the studies were carried out using reference strains, especially in case of the initial screening, but more recently, such assays also include clinical strains, both antimicrobial susceptible and resistant. Table 1 summarizes relevant data on the ability of herbal extracts to

In spite of extensive research carried out on healing effects of plants, antibacterial effects included, the subject is far from being closed, the high variety of plant species providing a strong support for investigation. Although numerous researchers deal with the effects of individual compound against bacteria, those extracts containing multiple active substances and exerting simultaneously antibacterial and immune-enhancing effects are favored. Veterinary and zoonotic pathology, due to the presence of MDR bacteria, could equally benefit of the discovery of plant extracts with high antibacterial potential, useable separately or in combina-

to antibiotic treatment, as mentioned in the literature [86].

tion with otherwise inefficient classical antibacterial therapies.

inhibit MDR zoonotic strains of animal origin.

5. Conclusions

to generalized [23, 24].


Table 1. Herbal extracts demonstrated to inhibit MDR zoonotic strains of animal origin.

Other well-known plants, which share immunological activity, from Compositae family, were further investigated for their antibacterial effects, following the principle of "the more the merrier." Echinacea, a popular plant in human medicine for its immune-stimulating and antiviral effects, also acts as an inhibitor for both tissue and bacterial hyaluronidase. This activity was considered to hinder the development and spreading of infection from localized to generalized [23, 24].

Another plant family, the Lamiaceae, has numerous examples of species with antibacterial activity. The investigation of their antibacterial activity against MDR, extended spectrum beta-lactamase-positive (ESBL), Gram-negative clinical isolates (A. baumannii, K. pneumoniae, E. coli, P. aeruginosa) of ethanolic extracts of Mentha sp., Ocimum basilicum, Plectranthus barbatus, and Rosmarinus officinalis, indicated that the minimal inhibiting concentration ranged from 0.5 to 2 mg/mL, while all extracts were effective against at least two of the tested bacteria [85].

Another plant from Lamiaceae with a less investigated antibacterial influence was considered as a potential therapeutic resource in bovine mastitis. Mastitis, one of the most economically impacting diseases of dairy cows due to subclinical status and difficult diagnosis, is heavily treated with antibiotics, leading to MDR in the involved bacterial strains. The lesser antibiotic efficacy, therefore, demands for therapeutic alternatives. In a study on the antimicrobial effectiveness of Melissa officinalis on the subclinical mastitis, microbiome carried out on several Romanian dairy farms ([93]), a variety of bacteria (S. sciuri, Shigella spp. S. lentus, Acinetobacter baumannii, Chryseomonas luteola, Enterobacter cloacae, Escherichia vulneris, etc.) were isolated with an MAR index up to 0.8 against amoxicillin+clavulanate, amoxicillin, chloramphenicol, cefoperazone, ciprofloxacin, and oxytetracycline. The Melissa tincture was less effective than the same plant essential oil (11.3 3.6 versus 12.3 4.3 mm), but comparable to amoxicillin, amoxicillin/clavulanic acid, and was higher than cefoperazone (total resistance). The efficacy depended more on the strain than on the solvent type also suggesting a therapeutic alternative to antibiotic treatment, as mentioned in the literature [86].

Most of the studies were carried out using reference strains, especially in case of the initial screening, but more recently, such assays also include clinical strains, both antimicrobial susceptible and resistant. Table 1 summarizes relevant data on the ability of herbal extracts to inhibit MDR zoonotic strains of animal origin.
